Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

Once-yearly zoledronic acid and days of disability, bed rest, and back pain: randomized, controlled HORIZON Pivotal Fracture Trial.

The objective of this study was to determine the effect of once-yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double-blind, placebo-controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15-minute intravenous infusion of zoledronic acid (5 mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were self-reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3-year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p = .0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p = .0017). In Cox proportional-hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR) = 0.94, 95% confidence interval (CI) 0.90-0.99] or limited activity owing to back pain (RR = 0.94, 95% CI 0.87-1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed-rest days owing to a fracture (RR = 0.58, 95% CI 0.47-0.72) and 7 or more limited-activity days owing to a fracture (RR = 0.67, 95% CI 0.58-0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once-yearly infusion with zoledronic acid over a 3-year period significantly reduced the number of days that patients reported back pain, limited activity owing to back pain, and limited activity and bed rest owing to a fracture.

Beliefs about and attitudes toward gambling in French-speaking Switzerland.

The present study aims to analyze attitudes and beliefs of the French-speaking general Swiss population (n = 2500; female n = 1280; mean age = 43 years) as regards gambling, which are to date almost exclusively studied in the North American and Australian contexts. Beliefs related to gambling include the perception of the effectiveness of preventive measures toward gambling, the comparative risk assessment of different addictive behaviors, the perceived risks of different types of gambling and attitudes are related to the gambler's personality. The general population perceived gambling rather negatively and was conscious of the potential risks of gambling; indeed, 59.0% of the sample identified gambling as an addictive practice. Slot machines were estimated to bear the highest risk. Compared with women and older people, men and young people indicated more positive beliefs about gambling; they perceived gambling as less addictive, supported structural preventive measures less often, and perceived gambling as a less serious problem for society. Gamblers were more likely to put their practices into perspective, perceiving gambling more positively than non-gamblers. General population surveys on such beliefs can deliver insights into preventive actions that should be targeted to young men who showed more favorable views of gambling, which have been shown to be associated with increased risk for problematic gambling.

Profile order and time-dependent artifacts in contrast-enhanced coronary MR angiography at 3T: origin and prevention.

To enhance the clinical value of coronary magnetic resonance angiography (MRA), high-relaxivity contrast agents have recently been used at 3T. Here we examine a uniform bilateral shadowing artifact observed along the coronary arteries in MRA images collected using such a contrast agent. Simulations were performed to characterize this artifact, including its origin, to determine how best to mitigate this effect, and to optimize a data acquisition/injection scheme. An intraluminal contrast agent concentration model was used to simulate various acquisition strategies with two profile orders for a slow-infusion of a high-relaxivity contrast agent. Filtering effects from temporally variable weighting in k-space are prominent when a centric, radial (CR) profile order is applied during contrast infusion, resulting in decreased signal enhancement and underestimation of vessel width, while both pre- and postinfusion steady-state acquisitions result in overestimation of the vessel width. Acquisition during the brief postinfusion steady-state produces the greatest signal enhancement and minimizes k-space filtering artifacts.

Prevalência e fatores associados à depressão entre idosos institucionalizados: subsídio ao cuidado de enfermagem

Este estudo teve como objetivo a verificação de depressão entre idosos institucionalizados. Empregou-se o método transversal utilizando-se a Escala de Depressão Geriátrica de Yesavage em cinco instituições de longa permanência do Distrito Federal para verificar sintomas de depressão. Foram estudados ao todo 299 indivíduos. Destes, 181 não atenderam os critérios de inclusão e 16 se recusaram a participar do estudo. Dos 102 idosos com condições de participar do estudo, 49,0% apresentavam depressão. Destes, 36,3% com depressão leve a moderada e 12,7% com depressão severa. Verificou-se associações entre sintomas de depressão e aumento da idade, sexo feminino, limitação/dependência e insatisfação com a instituição. Houve ainda associação significativa entre depressão e insônia, taquicardia, parestesia, tontura e suor excessivo. A depressão é altamente prevalente entre idosos institucionalizados, é mais comum entre as mulheres, e relaciona-se a uma série de sinais e sintomas que podem auxiliar em um diagnóstico precoce, subsidiando uma assistência de enfermagem mais efetiva.

Solid pseudopapillary tumor of the pancreas in children : typical radiological findings and pathological correlation

Introduction : Les tumeurs solides pseudo-papillaires du pancréas (SPT) sont des tumeurs rares, d'étiopathogénie encore incertaine.Le but de notre travail était de décrire les caractéristiques radiologiques des SPT dans le groupe d'âge pédiatrique et d'étudier leur corrélation avec les études anatomopathologiques en vue d'établir un diagnostic.Patients et Méthodes : Nous avons étudié rétrospectivement trois malades pédiatriques pour lesquelles le diagnostic de tumeur solide pseudo-papillaire du pancréas a été porté à l'examen d'une pièce opératoire. Ce groupe comprenait 3 jeunes filles et femmes (âge médian: 13 ans).Résultats : La tumeur a été découverte pendant le bilan de symptômes digestifs non spécifiques. Les examens biologiques n'étaient pas informatifs. Des investigations radiologiques complètes ont été réalisées y compris les ultrasons (US), la tomodensitométrie (CT) et l'imagerie par résonance magnétique (IRM).Celles-ci ont montré de volumineuses lésions nodulaires, peu vascularisées, de compositions habituellement hétérogènes, avec des composantes kystiques et hémorragiques identifiées dans les 3 cas. Un traitement chirurgical a été pratiqué chez toute les patientes. L'étude de la pièce opératoire a montré une tumeur encapsulée dans les 3 cas. Aucune métastase n'a été mise en évidence.Conclusion : Les SPT doivent être considérées dans le diagnostic différentiel des masses pancréatiques pédiatriques, en particulier chez les adolescentes. Certaines caractéristiques radiologiques comme des masses volumineuses bien circonscrites, des lésions hétérogènes avec des zones kystiques et hémorragiques, de plus entourées d'une pseudocapsule fibreuse réactive, suggèrent fortement le diagnostic de SPT. Celui-ci devrait ensuite être confirmé par une biopsie avant que la résection chirurgicale soit effectuée. Chez les enfants, Γ écho graphie abdominale reste la méthode de première intention, suivie par l'IRM comme technique d'imagerie de choix pour évaluer les caractéristiques et l'extension de la lésion, tout en évitant l'exposition des patients aux rayonnements ionisants.

Novel mutation in the tyrosine kinase domain of FGFR2 in a patient with Pfeiffer syndrome.

Mutations in the fibroblast growth factor receptor 2 (FGFR2) cause a variety of craniosynostosis syndromes. The mutational spectrum tends to be narrow with the majority of mutations occurring in either exon IIIa or IIIc or in the intronic sequence preceding exon IIIc. Mutations outside of this hotspot are uncommon and the few identified mutations have demonstrated wide clinical variability, making it difficult to establish a clear-cut genotype-phenotype correlation. To better delineate the clinical picture associated with these unusual mutations, we describe a severely affected patient with Pfeiffer syndrome and a missense mutation in the tyrosine kinase (TK) domain of FGFR2.

Paisagens Naturais” como Recursos Turísticos: o caso do Parque Natural de Serra da Malagueta na Ilha de Santiago, Cabo Verde

Esta dissertação coloca em evidência o valor das “Paisagens Naturais” como recursos turísticos, sendo o estudo de caso é o parque natural de Serra da Malagueta, em Cabo Verde, ilha de Santiago. A consciencialização da necessidade de preservar os valores naturais (assumida na actividade turística a partir de 1993, com elaboração da Agenda 21), necessidades psicológicas de encontrar alternativas para lazer e recreio diferentes das dos centros urbanos, necessidade de contacto com formas simples de viver e a busca de uma maior interacção com a Natureza, são factores que influenciaram o surgimento do turismo sustentável, o que valorizou a “Paisagem Natural” que pode ser encontrado nos parques naturais. Os componentes dos parques naturais constituem ofertas potenciais para actividades alternativas de lazer e recreio, daí utilizadas para diversas actividades turísticas de Natureza. A sua concretização implica a intervenção humana para ordenar os usos relativamente às componentes naturais, o que implica a criação de serviços básicos (informação, alojamento, restauração, animação cultural, ambiental). Tal tem conduzido a que alguns parques naturais tenham evoluído de simples recurso natural para destinos turísticos. A sua gestão como destinos turísticos deve complementar a gestão dos processos naturais que ali têm origem, por isso no seu planeamento devem ser incluídas acções de formação dos intervenientes. Este procedimento aumentará a eficácia das actividades turísticas e minimizar-se-á os aspectos negativos, que poderão advir do uso público dos parques naturais, de modo a serem pólos de desenvolvimento local pela sua diferenciação como produtos turísticos, relativamente aos convencionais. Esta deve ser uma das vias a ser seguida em Cabo Verde, pois predomina o turismo de sol e praia. O turismo cultural e de Natureza aparecem como “produtos secundários”, o que não tem favorecido a integração dos diversos parques naturais. Contudo, é frequente encontrar alguns operadores turísticos nacionais a enviarem os turistas aos parques naturais para visitas, mas alguns são usados só como pontos de passagem. Tal deve-se à inexistência de ofertas de alojamento, restauração e animação, o que não tem trazido nenhum benefício para as comunidades locais, situação verificada no parque natural de Serra da Malagueta, objecto deste estudo. Para inverter esta tendência as intervenções devem passar pela instalação dos serviços em falta, regulamentar as actividades do turismo de Natureza, envolver a população local e promover o conhecimento do parque natural junto dos consumidores turísticos.

Emäntä Olga Anttonen 13/4 1967

Kirje 13.4.1967